title: Antibody-mediated delivery of interleukin-2 to the stroma of breast cancer strongly enhances the potency of chemotherapy.
abstract: OBJECTIVE
  There is an interest in the discovery of biopharmaceuticals, which are well tolerated and which potentiate the action of anthracyclines and taxanes in breast cancer therapy.
  
  
  METHODS
  We have produced a recombinant fusion protein, composed of the human antibody fragment scFv(F16) fused to human interleukin-2 (F16-IL2), and tested its therapeutic performance in the MDA-MB-231 xenograft model of human breast cancer. The F16 antibody is specific to the alternatively spliced A1 domain of tenascin-C, which is virtually undetectable in normal tissues but is strongly expressed in the neovasculature and stroma of breast cancer.
  
  
  RESULTS
  When used as monotherapy, F16-IL2 displayed a strikingly superior therapeutic benefit compared with unconjugated recombinant IL-2. The administration of doxorubicin either before (8 days, 24 h, or 2 h) or simultaneously with the injection of F16-IL2 did not decrease the accumulation of immunocytokine in the tumor as measured by quantitative biodistribution analysis. Therapy experiments, featuring five once per week coadministrations of 20 mug F16-IL2 and doxorubicin, showed a statistically significant reduction of tumor growth rate and prolongation of survival at a 4 mg/kg doxorubicin dose but not at a 1 mg/kg dose. By contrast, combination of F16-IL2 with paclitaxel (5 and 1 mg/kg) exhibited a significant therapeutic benefit compared with paclitaxel alone at both dose levels. F16-IL2, alone or in combination with doxorubicin, was well tolerated in cynomolgus monkeys at doses equivalent to the ones now used in clinical studies.
  
  
  CONCLUSIONS
  F16-IL2 may represent a new useful biopharmaceutical for the treatment of breast cancer.
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Switzerland.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mårlind
authors.forename: Manuela
authors.initials: M
authors.lastname: Kaspar
authors.forename: Eveline
authors.initials: E
authors.lastname: Trachsel
authors.forename: Roberto
authors.initials: R
authors.lastname: Sommavilla
authors.forename: Stuart
authors.initials: S
authors.lastname: Hindle
authors.forename: Camilla
authors.initials: C
authors.lastname: Bacci
authors.forename: Leonardo
authors.initials: L
authors.lastname: Giovannoni
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007128:Immunoglobulin Fragments / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*; D019063:Tenascin / Q000008:administration & dosage / Q000276:immunology*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D007128:Immunoglobulin Fragments; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D019063:Tenascin; D004317:Doxorubicin; D017239:Paclitaxel